Pluripotent Stem Cell-Based Drug Screening Reveals Cardiac Glycosides as Modulators of Myotonic Dystrophy Type 1

• Main Authors: Yves Maury, Pauline Poydenot, Benjamin Brinon, Lea Lesueur, Jacqueline Gide, Sylvain Roquevière, Julien Côme, Hélène Polvèche, Didier Auboeuf, Jérome Alexandre Denis, Geneviève Pietu, Denis Furling, Marc Lechuga, Sandrine Baghdoyan, Marc Peschanski, Cécile Martinat
• Format: Article
• Language: English
• Published: Elsevier 2019-01-01
• Series: iScience
• Online Access: http://www.sciencedirect.com/science/article/pii/S2589004218302499

Summary: There is currently no treatment for myotonic dystrophy type 1 (DM1), the most frequent myopathy of genetic origin. This progressive neuromuscular disease is caused by nuclear-retained RNAs containing expanded CUG repeats. These toxic RNAs alter the activities of RNA splicing factors, resulting in alternative splicing misregulation. By combining human mutated pluripotent stem cells and phenotypic drug screening, we revealed that cardiac glycosides act as modulators for both upstream nuclear aggregations of DMPK mRNAs and several downstream alternative mRNA splicing defects. However, these occurred at different drug concentration ranges. Similar biological effects were recorded in a DM1 mouse model. At the mechanistic level, we demonstrated that this effect was calcium dependent and was synergic with inhibition of the ERK pathway. These results further underscore the value of stem-cell-based assays for drug discovery in monogenic diseases. : Physiology; Molecular Biology; Cell Biology Subject Areas: Physiology, Molecular Biology, Cell Biology